The present invention relates to N-substituted tricyclic 3-aminopyrazoles as inhibitors of tubulin polymerization and for use in treating solid tumors.
Malignant solid tumors are a leading cause of death throughout the world. There is a tremendous need for more efficacious treatments for all cancers. Currently, cancer is treated with a triad of approaches that include surgery, radiation and chemotherapy or, in most cases a combination of these treatment modalities. Existing chemotherapeutics kill tumor cells directly, but have relatively poor long-term efficacy in most cancers, are usually associated with debilitating side-effects (hematological, nausea, weight loss, neurotoxicity in the case of paclitaxel) and cannot be administered chronically. Advanced cancers are prone to develop resistance to chemotherapy due to their inherent genetic instability. For this reason, a good deal of current drug discovery research seeks to understand the mechanism(s) responsible for the development of multi-drug-resistant tumor phenotypes and to identify agents that are capable of over-coming this treatment-related resistance.
Particular interest has focused on discovery of novel agents that demonstrate activity in taxane and multi-drug resistant tumors and are capable of inhibiting angiogenesis by also targeting key processes involved in the process of tumor-induced angiogenesis.
Formation of new blood vessels within growing tumors appears to be an absolute requirement for tumor growth beyond a few millimeters and for the process of metastasis. Increased tumor vessel density compared to normal tissues has been demonstrated in many different tumors including colon, breast, lung and brain. In several studies, vessel density has correlated with disease progression and severity, and intratumor vascularity was an independent prognostic indicator.
The close interplay between angiogenesis and metastasis contributes to the poor prognosis of patients with highly angiogenic tumors. In the normal adult, vascular endothelium is quiescent, and active proliferation of endothelium for new blood vessels is limited to tumor tissues, wound healing or endometrial turnover.
Anti-angiogenic therapy has the potential to provide long-term suppression of tumor growth and metastasis without severe systemic toxic side effects or the development of resistance to therapy. Avastin (anti-VEGF), approved by the FDA in 2004, is effective at increasing the survival of stage III colorectal cancer patients, and has provided validation for the use of angiogenesis-targeted agents in cancer.
Microtubules are cytoskeleton protein polymers comprised of α-tubulin and β-tubulin polymers that are vital components of all cells and are critical for the maintenance of cell morphology. Microtubules form the basis of the mitotic apparatus in cells, and dynamically functioning microtubules are critical for normal cell division, as well as cell movement and attachment. Interference with microtubule dynamics prevents dividing cells from proceeding normally through the cell cycle and leads to G2/M cell cycle arrest and apoptosis.
Cancer cells acquire unlimited replicative potential and continually divide without going into quiescence or senescence. As a result of this uncontrolled growth, tumor cells are extremely dependent upon microtubule dynamics and, thus are susceptible to agents that interfere with microtubule dynamics either through stabilization of microtubule polymers or by inhibiting microtubule polymerization.
In addition, recent publications have demonstrated that proliferating endothelial cells involved in tumor-induced angiogenesis are also sensitive to the anti-mitotic action of tubulin modulators. These findings suggest that novel microtubule inhibitors, such as the compounds of the present invention, may impart dual anti-angiogenic and anti-tumor cell activities resulting in improved efficacy versus a broad range of tumor types.
Tubulin binding agents are one of the most successful classes of anti-cancer drugs in clinical use. However, the clinical usefulness of the current agents known in the art, such as paclitaxel (Taxol™), is limited by inherent resistance of many tumor types and by acquired resistance which develops in a high percentage of patients following multiple cycles of therapy. In addition, the side-effects of these agents are significant (e.g. myelosuppression, neurotoxicity) and can be dose-limiting either due to the compound itself or the vehicle required for intravenous administration. None of the currently approved agents are orally bioavailable.
Thus, identification of novel, orally active agents that target microtubules in proliferating tumor cells and in activated pro-angiogenic endothelial cells, together with demonstrated activities in multi-drug resistant tumor models and with improved side-effect profiles, remains among the most promising approaches for development of new anti-cancer drugs.
Currently, two main classes of anti-microtubule, anti-mitotic compounds are used clinically. Both classes differ from the compounds of the present invention by the mode of their interaction (binding) with microtubules.
The taxanes (paclitaxel and docetaxel) and epothilones (there are no approved epothilones) bind primarily to α-tubulin on microtubule polymers at the so-called taxane-binding site, stabilize existing microtubules and prevent depolymerization, thus forming stable, non-functional microtubules. In contrast, the Vinca alkaloids (vinblastine, vincristine and vinorelbine) bind to the tubulin polymer at the Vinca domain, inhibit the formation of new microtubules and thus inhibit formation of the necessary mitotic assembly required for cell division.
During the M-phase of the cell cycle, the dynamic microtubules that comprise the cell mitotic spindle are the target of most of the known tubulin-directed agents. Colchicine and the Vinca alkaloids bind to free β-tubulin and inhibit its polymerization into microtubules. Taxanes and epothilones bind to β-tubulin on the microtubules and prevent depolymerization, leading to uncontrolled microtubule formation. Both mechanisms lead to disruption of the mitotic spindle, metaphase arrest and subsequent apoptosis.
Although the ultimate mechanism of action of the various anti-mitotic agents is essentially the same (i.e. disruption of normal microtubule formation and dynamics), there are dramatic differences in the activity of the various agents against different cancer types. For example, the Vinca alkaloids, vinblastine, vincristine and vinorelbine, are generally more efficacious against hematological cancers and less effective versus solid tumors. In contrast, the taxanes, paclitaxel and docetaxel, are effective against ovarian, breast and lung solid tumors, but are relatively ineffective versus solid tumors of the colon, kidney and hematological cancers. A third class of anti-mitotic agents represented by colchicine, also inhibits tubulin polymerization by binding at the colchicine binding site, however none of these compounds have been used successfully in the oncology clinical arena due to extreme toxicity at efficacious doses and an extremely narrow therapeutic window. Accordingly, identification of orally active, small molecule anti-tubulin, anti-mitototic agents with less hematological and neuropathic toxicity and demonstrated activity in paclitaxel- and multi-drug (MDR)-resistant tumors, agents such as the compounds of the present invention, is critical to fulfilling the hereto unmet clinical need.
Systemic chemotherapy with cytotoxic agents has been the standard therapeutic approach to treating cancer known in the art. The majority of these chemotherapeutic compounds are microtubule inhibitors or DNA-damaging agents that are designed to kill rapidly dividing cells indiscriminately. In most cases, these agents are administered as a single bolus iv or short courses of therapy at the maximum tolerated dose (MTD). Because of adverse side-effects, this type of therapeutic approach requires fairly long dosing holidays (generally 2-3 weeks) between successive dosing cycles to allow recovery from the many toxicities associated with MTD-based therapy, including acute myelosuppression, loss of hair, GI-related side-effects, nausea and other adverse reactions. Supportive care is also frequently required to assist the patient's recovery from MTD-based therapy.
More recently, with the recognition that conventional cytotoxics also affect the endothelium of growing tumor vasculature at lower, relatively non-toxic doses, there has been a shift in the dosing paradigm toward using continuous, low non-MTD doses as an alternative approach to optimize the anti-angiogenic component of chemotherapy. This concept of administering low doses of chemotherapeutic drugs on a frequent or continuous schedule with no extended interruptions in therapy is known as ‘metronomic chemotherapy’. In recent reports, the anti-angiogenic efficacy of metronomic dosing has been reported to yield significant clinical benefit without MTD-related toxicities. The compounds of the present invention present potent, orally active, colchicine-competitive inhibitors of tubulin polymerization. Accordingly, identification of orally active, small molecule anti-tubulin, anti-mitototic agents suitable for metronomic dosing, such as the compounds of the present invention, is critical to meeting the current clinical needs.
Secondary tumors are typically treated with aggressive chemotherapy or radiation. However, no approved therapies are currently directed toward blocking the deadly metastatic process. Potential intervention points in metastasis include tumor cell intravasation, extravasation, survival and proliferation within the target organ, and angiogenesis. Accordingly, the compounds of the present invention, however, by virtue of their dual anti-proliferative and anti-angiogenic activities, are useful for the prevention of metastases.
The published WO 2003097609 (2003) discloses similar tricyclic 3-aminopyrazoles. However, the instant application is directed to the compounds having the following structures:
which exhibit surprisingly superior activity over the compounds in the reference.